This proposal seeks to implement a novel, systematic approach to study the iontophoretic transport properties of human skin. The effect of physical- chemical factors such as molecular size and charge of the permeant, ionic strength and pH of the electrolyte and mode of iontophoresis (pulsed versus steady d.c) on the flux of the permeant will be systematically investigated using the four electrode iontophoretic diffusion cell system. The applicability of theoretical models of iontophoretic transport, incorporating the effect of these physical-chemical factors, to human skin will be critically examined. These studies will contribute to a better understanding of iontophoresis from a fundamental standpoint and a fuller exploitation of its therapeutic potential for the controlled transdermal delivery of small permeants. A synergism of iontophoreses and a well tolerated chemical size limitations to the transdermal delivery of polypeptides. A comprehensive, mechanistic understanding of how both technologies, separately and synergistically, influence the transport properties of skin to polypeptides will be established. In vivo studies will be conducted to establish the feasibility of a combination of a well tolerated chemical permeation enhancer and iontophoresis for the sustained transdermal delivery of leuprolide, a LHRH analog, for systemic effect (suppression of testosterone levels). Use of iontophoresis and a permeation enhancer to modulate the input characteristics by providing a periodic pulse of the native LHRH to elicit the desired pharmacological effect (stimulation of LH and FSH secretion) will also be explored.